1. Field of the Invention
This invention relates to methods and apparatus for administering substances by iontophoresis. More particularly, the present invention discloses methods and apparatus for administering determinable quantities of medicaments and the like by iontophoresis in a safe and efficient manner.
2. The Background of the Invention
The process of iontophoresis was reported as early as about 1740 for use in applying medication locally through a patient's skin and later in about 1900 for use in delivering medicaments to the eyes and ears. In its simplest terms, this technique involves the application of an electromotive force to drive ionic chemicals through the skin so that they can be absorbed by the adjacent tissues and blood vessels. By iontophoretic techniques, various substances (including some pharmaceuticals and medicaments) have been administered to a patient without the necessity of a hypodermic injection and without the associated problems, such as pain, the risk of infection, and trauma to the patient.
While iontophoresis has been the subject of continuous experimentation for many years, the process has not been used to any major extent by medical practitioners. Iontophoresis has been tested for use in treatments such as the application of local anesthetics, the application of medication for treatment of skin disorders, and the application of other limited types of medications in order to achieve a localized effect.
As mentioned above, iontophoresis involves the application of an electromotive force to drive ions through the skin. Accordingly, ions bearing a positive charge are driven into the skin at the anode of an electrical system, and ions bearing a negative charge are driven into the skin at the cathode of the electrical system. For example, positively charged ions such as zinc, copper, alkaloids, anesthetics, and certain vasodilating drugs are introduced into the skin or the mucous membranes from the positive pole. On the other hand, a negatively charged drug, such as salicylate, can be driven into the skin using the negative pole.
Some drugs have exhibited their effect at the site of iontophoresis, where they are initially introduced through the skin. Examples of such drugs which exhibit localized systemic effects upon iontophoresis through the skin are local anesthetics.
Various other drugs can be administered to exhibit systemic effects by iontophoretically driving the drug into the circulatory system. In such cases, the ions transferred through the skin are absorbed into the blood stream and enter the body's general blood circulatory system.
Iontophoretic delivery of medicaments can provide significant benefits over other methods of delivery. For example, when a medicament is taken orally, it must be absorbed through the digestive tract. However, uptake of the medicament through the digestive tract varies greatly from individual to individual. Moreover, the drug must pass through the liver where it is not unusual for upwards of 70% of the drug to be inactivated on the first pass through the liver. Thus, iontophoresis is capable of avoiding this "first pass effect" in the administration of certain medicaments. In addition, patient discomfort, noncompliance, and the risk of infection associated with injections are also eliminated when using iontophoresis.
While iontophoresis has been applied to many different drugs, it has never established itself as a widely used method for the delivery of medicaments. This was partly caused by the use of poor equipment and the lack of understanding of the mechanism of iontophoresis and its potential safety hazards. This historic view of iontophoresis, however, began to change somewhat in about 1959.
At that time, a test was devised, using iontophoresis, to diagnose cystic fibrosis. It was found that pilocarpine could be iontophoretically administered onto localized areas of skin so as to induce sweating. The sweat could then be collected and tested for abnormal levels of sodium or chloride, which is diagnostic of cystic fibrosis. This technique met with approval and was eventually selected by the Cystic Fibrosis Foundation as the standard and only acceptable test for diagnosing cystic fibrosis.
The widespread use of iontophoresis in diagnosing cystic fibrosis has resulted in some noticeable improvements in the equipment used to supply electrical current and in the electrodes used in iontophoretic applications. This use of iontophoresis has also led to some additional understanding of the mechanisms involved in iontophoresis. However, outside the field of cystic fibrosis diagnosis, the technique has yet to receive widespread acceptance.
Notwithstanding the limited acceptance of iontophoresis, the potential uses of iontophoresis can be readily appreciated from the previous discussion. Iontophoresis can obviously be used to introduce medicaments and other substances into the body without the necessity of an injection. Its use could thus become extremely significant in administering drugs and pharmaceuticals where frequent injections are required.
Frequent injections over a prolonged period of time as a form of treatment have several disadvantages. Many individuals find it difficult to adjust to the requirement of multiple daily injections, which are painful, carry the risk of infection, and cause additional strain on their already taxed system, possibly modifying the effects of the drug.
Iontophoresis as an alternative to existing methods of administration of medicaments has several advantages. The use of iontophoresis to administer such substances results in a high percentage of the substance actually reaching the systemic circulation--this is in direct contrast to oral administration where the drug is subject to the irregularities of the digestive process and possible inactivation by the liver prior to being absorbed into the systemic circulatory system. As a result, a relatively large quantity of a drug must be ingested orally in order to obtain the desired concentration of the drug in the bloodstream and to achieve the desired therapeutic effect. It will be appreciated that since each patient's digestive system functions differently, the amount of an orally ingested drug needed to achieve the desired therapeutic effect is often difficult to predict.
Another potential advantage of iontophoresis is the ability to administer medicaments over a sustained period of time without invasion of the body. Optimally, it is often desirable to maintain a certain constant level of medicament within the patient's system, instead of periodically injecting a bolus of medicament. However, due to limitations in the presently available iontophoresis systems, this sustained delivery is not practical because of the danger of electrical and chemical burns to the patient.
Another possible advantage of iontophoresis is the potential ability to deliver medicaments to a patient without also introducing sodium and other similar ions. Many medications exist as sodium salts, and solutions of these medications may contain a relatively large quantity of sodium which is an undesirable species for delivery to a patient who is suffering from cardiovascular or renal problems.
While the use of iontophoresis has many potential benefits, traditional iontophoretic techniques have suffered several drawbacks such that the iontophoretic administration of medicaments has not been generally very practical. In particular, traditional techniques for iontophoresis have been considered unsafe, unpredictable, inconvenient, or uneconomical. It is for these reasons that iontophoresis has not enjoyed widespread acceptance in the medical field. Moreover, due to the short duration of administration, iontophoresis has been almost exclusively used to administer locally active medicaments.
With respect to safety, it is found that iontophoresis may result in burns to the patient's skin. These burns stem from two sources: (1) galvanic sources where the electrical current itself causes burns, and (2) chemical sources where extremes in pH (which develop during the iontophoresis process) act in conjunction with electric current to result in chemical burns.
Methods and procedures have been developed to control serious galvanic burns and other electrical hazards. For example, it has been suggested that the electrical current used in the iontophoretic process be increased slowly and that limitations be placed on the amount of current delivered.
Galvanic burns can also be minimized or reduced by keeping the current density per unit area of skin below threshhold values at which burning begins. Low current densitites can be achieved by attention to techniques of iontophoresis, such as avoiding folds or wrinkles between the electrode and the skin (which cause high localized current density resulting in burns), using a gel-moistened electrode pad in connection with the electrode, and moistening the skin prior to and during iontophoresis. A further suggestion in the art has been to increase the surface area of the electrode so that the current is spread over a larger area, thereby reducing current density. See U.S. Pat. No. 4,416,274 (Jacobsen et al.) entitled "Ion Mobility Limiting Iontophoretic Bioelectrode," and U.S. Pat. No. 4,477,971 (Jacobsen et al.) entitled "Iontophoretic Electrode Structure."
It is more difficult to control pH and the resulting burns caused by extremes in the alkalinity or acidity of the medicament solution during passage of electric current. As the current passes between the electrode contact and the medium containing medicament, there is increased production of hydrogen ions (H.sup.+) or hydroxide ions (OH.sup.-). When the iontophoresis electrode is "inert," this increase in concentration is caused by the exchange of charge through the electrolysis of water.
Since the H.sup.+ and OH.sup.- ions which result from the electrolysis of water are extremely mobile, they migrate rapidly through the solution away from the electrode and toward the skin of the patient. Thus, an area of extreme pH is ultimately created directly adjacent to the skin. This area of extreme pH is clearly dangerous and has been observed to cause serious burns when the current causes these ions to pass through the skin. Thus, the decrease changes in pH imposes a time limit on the duration of treatments, usually about twenty (20) to thirty (30) minutes.
Attempts have been made to control pH in the iontophoretic system. Heretofore, attempts are less than satisfactory. One method of attempting to control pH has been to introduce a buffer into the iontopheretic system. The introduction of buffers, however, is found to defeat some of the important useful features of iontophoresis.
The introduction of buffers results in increasing concentrations of additional ionic species within the system. In a solution containing a mixture of ions, the quantity of a specific ion that will be moved by a given electromotive force is proportional to (a) the concentration of the ion, (b) the mobility of the ion (lighter, less massive ions generally are more mobile), and (c) the valence charge on the ion.
Typically, the buffer ions which are usually small and very mobile (such as phosphate ions, and complementary cations such as sodium) will migrate through the solution at a much faster rate than will the larger ions (such as drug molecules) which are the medicament ions to be transported through the skin of the patient by the iontophoretic process. The result is that a large percentage of buffer ions may be driven into the skin by iontophoresis instead of the desirable medicament ions. Thus, the quantity of medicament molecules driven through the skin is seriously reduced and the quantity of undesirable ions driven through the skin is increased.
Moreover, as would be expected from the foregoing, the use of buffers aggravates the problem of quantification of the amount of medicament delivered in any given iontophoretic administration. If buffer ions are forced through the skin, it will be difficult or impossible to determine how much of the medicament has passed through the skin. This is particularly true since most medicament ions, especially drug ions, are larger, and slower in the electrical field created during the iontophoresis process than are the smaller buffer ions.
The existing literature has pointed out that administration of substances by ion transfer long has been regarded as one of the least accurate methods of administration. Indeed, the lack of accurate quantification techniques has been, and still is, one of the major objections to wide acceptance of iontophoresis.
A further problem encountered in the clinical use of iontophoresis is that iontophoresis systems have not been particularly convenient or economical. Generally, other methods of administration of medicaments have been less expensive and easier to use. Considerations of cost and convenience have, therefore, also impeded the general acceptance of iontophoresis.
As can be appreciated from the above discussion, the technique of iontophoresis has several major potential benefits for use in the medical area. Iontophoresis offers a technique whereby medicaments such as drugs may be introduced into the body noninvasively. That is, the patient may receive a needed medication without the necessity of an injection of a bolus of medicament and without the unknowns associated with the "first pass effect" of oral administration. Moreover, iontophoresis has the potential of providing a method whereby continuous, sustained doses of medications may be administered.
Despite this potential for iontophoretic administration techniques, the present state of iontophoresis is such that it is not particularly safe, since both galvanic and pH-induced burns are common. While galvanic burns can, to a certain extent, be controlled by appropriate techniques known in the art, pH-related burns associated with the passage of electrical current through the solution remain problematic. These burns are painful and difficult to heal.
In addition, existing methods and apparatus do not provide for adequate quantification of the medicament being administered. This is caused in large measure by the H.sup.+ and OH.sup.- ions produced during iontophoresis. These highly mobile ions compete with the larger, less mobile medicament molecules for introduction in the patient, thereby resulting in an inability to determine how much of the medicament actually reaches the patient. At the same time, iontophoresis has not traditionally been particularly economical or convenient.
Thus, what is needed in the art is a technique for iontophoretically administering medicaments and other substances to the body in such a manner that burns and other safety hazards to the patient are avoided. It would be a significant advancement to provide improved methods and apparatus for administration of a medicament using iontophoresis which would allow the amount of the medicament administered to be better quantified, controlled, and delivered for prolonged time periods (i.e., over a period of hours or even days).
It would be a further significant advancement in the art to provide such methods and apparatus for administering medicaments by iontophoresis which could operate safely without the addition of buffering ions. It would also be a significant advancement in the art if methods and apparatus could be provided for iontophoretic administration of medicaments which provided for close control of pH within the system. It would be still another advancement in the art to provide methods and apparatus for administration of medicaments using iontophoresis which are economical and convenient to use. Such methods and apparatus are disclosed and claimed herein.